Nucleophilic Addition of Phosphorus Ylides The Wittig Reaction

11 Nucleophilic Addition of Phosphorus Ylides The Wittig Reaction 

Aldehydes and ketones are converted into alkenes by means of a nucleophilic addition called the Wittig reaction. Fhe reaction has no direct biological counterpart but is important both because of its wide use in the laboratory and drug manufacture and because of its mechanistic similarity to reactions of the coenzyme thiamin diphosphate, which we ll see in Section 29.6. 

In the Wittig reaction, a phosphorus ylule, R2C—P(C6H5)3, also called a phosplionme and sometimes written in the resonance form R2C = P(C6H5)3, adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine. (An ylide—pronounced ill-id—is a neutral, dipolar compound with adjacent plus and minus charges. A betaine—pronounced bay-ta-een—is a neutral, dipolar compound with nonadjacent charges.) 

The betaine intermediate is not isolated rather, it spontaneously decomposes through a four-membered ring to yield alkene plus triphenylphosphine 

O The nucleophilic carbon atom of the phosphorus ylide adds to the carbonyl group of a ketone or aldehyde to give an alkoxide ion intermediate. 

The initial addition step appears to take place by different pathways depending on the structure of the reactants and the exact experimental conditions. One pathway involves a one-step cycloaddition process analogous to the Diels-Alder cycloaddition reaction (Section 14.4). The other pathway involves a nucleophilic addition reaction to give a dipolar intermediate called a betaine (bay-ta-een), which undergoes ring closure. 

The Wittig reaction is extremely general, and a great many monosubstituted, disubstituted, and trisubstituted alkenes can be prepared from the appropriate combination of phosphorane and aldehyde or ketone. Tetrasubstituted alkenes can t be prepared, however, because of steric hindrance during the reaction. 

The real value of the Wittig reaction is that it yields a pure alkene of predictable structure. The C=C bond in the product is always exactly where the C=0 group was in the reactant, and no alkene isomers (except E,Z isomers) are formed. For example, Wittig reaction of cyclohexanone with methylene-triphenylphosphorane yields only the single alkene product methylene-cyclohexane. By contrast, addition of methylmagnesium bromide to 

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Nucleophilic Addition of Phosphorus Ylide The Wittig Reaction... 

Addition of Hydrogen Halides to an Alkene Section 11.2 Addition of a Nitrogen Nucleophile to an Aldehyde or a Ketone Section 18.8 Figure 18.3 Addition of Phosphorus Ylides to an Aldehyde or a Ketone (The Wittig Reaction) Section 18.7 Figure 18.2... 

Dimsylsodium (24) functions as a highly basic sulfur ylide. It can be used to convert phosphonium salts to phosphorus ylides for use in the Wittig reaction. Dimsylsodium also reacts with aldehydes and ketones by nucleophilic addition to form epoxides and with esters by nucleophilic substitution to yield p-ketosulfoxides (25) (Scheme 11). The p-ketosulfoxides (25) contain acidic a-hydrogens which can be readily removed to allow alkylation, and the products (26) suffer reductive desulfuration on treatment with aluminium amalgam to yield ketones (27) (Scheme 11) This procedure can, for instance, be applied to the conversion of ethyl benzoate to propiophenone (28) (Scheme 12). 

Another useful reagent in nucleophilic additions contains a carbanion that is stabilized by an adjacent, positively charged phosphorus group. Such a species is called a phosphorus ylide, and its attack on aldehydes and ketones is called the Wittig reaction. The Wittig reaction is a powerful method for the selective synthesis of alkenes from aldehydes and ketones. 

The employment of phosphorus-stabilized carbon nucleophiles for alkene synthesis was initiated by the discovery of the Wittig reaction [10], which provides a convenient method for the preparation of a wide variety of polysubstituted alkenes with complete positional selectivity and generally high levels of geometrical control. Moreover, the phosphonium ylides used in the Wittig reaction are readily formed by the addition of suitable bases to the corresponding phosphonium salts, which are commonly prepared by treating alkyl halides with phosphines. 

Addition of thiamine. The conversion of pyruvate to acetyl CoA begins by reaction of pyruvate with thiamine pyrophosphate, a derivative of vitamin B, The hydrogen on the heterocyclic thiamine pyrophosphate is weakly acidic and can be removed by reaction with base to yield a nucleophilic ylide much like the phosphorus ylides u.sed in Wittig reactions /Section 19.12>. This nucleophilic yJide adds to the ketone carbonyl group of pyruvate to yield a tetrahedral intermediate. 

By far the main interest in the reaction of halo [ C] acetates with phosphorus nucleophiles is for the preparation of phosphoryl-stabilized carbanions for use in Wittig and related reactions. The presence of the additional electron-withdrawing ester group provides additional stabilization, significantly modifying the reactivity of the ylide species and the stereochemical course of its reactions. The two phosphorus reagents discussed here include the triphenylphosphonium salt type 158. precursors of Wittig methylenetriphe-nylphosphoranes, and the trialkylphosphonoacetate type 159. applied in the Horner-Wadsworth-Emmons family of reactions . ... 

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